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Current Molecular Pharmacology

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https://www.readbyqxmd.com/read/28183242/decoding-corticotropin-releasing-factor-receptor-type-1-crystal-structures
#1
Andrew S Doré, Andrea Bortolato, Kaspar Hollenstein, Robert K Y Cheng, Randy J Read, Fiona H Marshall
The structural analysis of class B G protein-coupled receptors (GPCR), cell surface proteins responding to peptide hormones, has until recently been restricted to the extracellular domain (ECD). Corticotropin-releasing factor receptor type 1 (CRF1R) is a class B receptor mediating stress response and also considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of human CRF1R in complex with the small-molecule antagonist CP-376395 in a hexagonal setting with translational non-crystallographic symmetry...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103786/crh-receptor-signalling-potential-roles-in-pathophysiology
#2
Styliani Ourailidou, Dimitris Grammatopoulos
To maintain homeostatic equilibrium, living organisms have evolved complex adaptation systems that control an array of behavioural, autonomic, neuroendocrine and immune responses. One of the important switches The master switch of this system is the hypothalamic hormone corticotropin-releasing hormone (CRH), which together with a family of related peptides (urocortins, UCNs) orchestrate stress-coping responses that reinstate homeostasis. Persistent disturbances in the homeostatic equilibrium either due to inadequate or persistently uncontrolled responses have been associated with pathogenic mechanisms of disease...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103785/non-peptide-crf-receptor-antagonists-allosterism-kinetics-and-translation-to-efficacy-in-human-disease
#3
Dimitri E Grigoriadis, Samuel R J Hoare
G-Protein coupled receptors (GPCRs) have been, and remain a key target of drug discovery programs for human disease. While many drugs have been developed that interact with these proteins in the simple classic manner - that is - physically blocking the cognate ligand from simply binding to its target receptor, drug discovery approaches have elucidated alternative more complex methods by which small molecules can interact with these receptors and block their function. This is most evident in the Class B GPCRs where the cognate ligands are relatively large peptides with multiple points of contact on the GPCR spanning both hydrophilic and hydrophobic domains on the same protein to elicit function...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103783/understanding-corticotropin-releasing-factor-receptor-crfr-activation-using-structural-models
#4
Arnau Cordomi, George Liapakis, Minos Timotheos Matsoukas
The corticotropin-releasing factor type 1 and 2 receptors (CRF1R and CRF2R) belong to the secretin-like family, also known as class B1, of G protein-coupled receptors (GPCRs). Several endogenous hormones mediate their responses through the CRF receptors, such as CRF and the urocortins. The structures for the N-terminus extracellular domain of both CRF1R and CRF2R in complex with peptidic ligands were released a few years ago and permitted the study of hormone binding to the orthosteric binding site. It was not until more recently, when the crystal structure of the transmembrane domain of human CRF1R in its inactive state bound to an allosteric antagonist became available...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103782/structures-of-the-first-extracellular-domain-of-crf-receptors
#5
Viviane Zelenay, Marilyn Perrin, Roland Riek
Corticotropin releasing factor (CRF) receptors belong to the secretin family of G protein-coupled receptors (GPCRs) and are responsible for initiating endocrine stress responses and mediating anxiety related behaviors upon activation via stressors. The main binding site for the CRF ligands is the first extracellular domain (ECD) of the receptors. Several structures of ligand-free and ligand-bound ECDs were recently determined either by nuclear magnetic resonance (NMR) spectroscopy or X-ray crystallography. They reveal how the ligands bind through both hydrophobic and hydrophilic interactions to the ECDs, which is highly dynamic in absence of ligands...
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103781/prospective-clinical-applications-of-crf-peptide-antagonists
#6
Jean E Rivier
It is noteworthy that thirty three years of efforts in corticotropin releasing factor (CRF) research by academia and the pharmaceutical industry resulted in several thousand papers and patents, yet little progress has been made to identify and market diagnostic or therapeutic CRF peptides and small molecule ligands. We document the potential relevance of CRF peptide antagonists to reinvigorate stress/anxiety affected "anatomy systems" in order to boost their efficacy.
January 10, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28103784/the-multi-faceted-profile-of-corticotropin-releasing-factor-crf-family-of-neuropeptides-and-of-their-receptors-on-the-paracrine-local-regulation-of-the-inflammatory-response
#7
Andrew N Margioris, Eirini Dermitzaki, Maria Venihaki, Christos Tsatsani, Achille Gravanis, Pavlina Avgoustinaki, George Liapakis
The corticotropin releasing factor (CRF) family of neuropeptides, CRF and the Urocortins, and their receptors are present not only within the central nervous system but also in the periphery at various locations and at the sites of inflammation where they influence its progress in a complex local / paracrine manner. These neuropeptides are either produced locally, by components of the inflammatory response or they may reach the inflammation sites via postganglionic sympathetic and sensory afferent nerve transport...
January 9, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28071586/milestones-in-crh-research
#8
George P Chrousos, Emmanouil Zoumakis
The Corticotropin-releasing Hormone (CRH) mammalian family members include CRH, urocortin I, Stresscopin (SCP) and Stresscopin-related peptide (SRP), along with the CRH receptors type 1 (CRHR1) and type 2 (CRHR2), and CRH-binding protein (CRH-BP). These family members differ in their tissue distribution and pharmacology. Several studies have provided evidence supporting an important role of this family in the regulation of the neuroendocrine and behavioral responses to stress. Regulation of the relative contribution of CRH and its homologs and the two CRH receptors in brain CRH pathways may be essential in coordinating physiologic responses to stress...
January 9, 2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/28034288/the-non-genomic-effects-of-the-ppar%C3%AE-%C3%AE-agonist-gw0742-on-stz-treated-rat-aorta
#9
Noelia Perez-Diaz, Igor Pushkarskya, Nadia Oweisa, Lisa A Lionea, Louise S Mackenzie
BACKGROUND: The ubiquitous nuclear receptor PPARβ/δ is increasingly being studied in regards to numerous diseases including diabetes following on the finding that PPARβ/δ agonist GW0742 controls Type 1 Diabetes in rats. Studies have shown that GW0742 has off target, non- PPARβ/δ effects in the cell although there are some key questions that remain to be addressed in respect to the significance of this control on vascular tone. METHODS: Using isometric organ baths, rat aorta rings were exposed to ROCK inhibitors and the changes in contraction and dilation measured...
December 29, 2016: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/27981901/molecular-insights-of-creb-and-map-k-phosphorylation-by-modafinil-in-wake-related-brain-areas
#10
Ramsés Jiménez-Moreno, Adrián Amaury Farret-Ramos, Adriana Valle-Ayala, Niurka Trujillo-Paredes, Eric Murillo-Rodríguez
BACKGROUND: Modafinil (MOD) is a waking-promoting compound that is used for treatment of sleep disorders such as sleepiness and narcolepsy. Despite its efficiency, there are missing pieces of evidence regarding the mechanism of action of MOD at molecular level. For example, current data have demonstrated that MOD induces alertness by activating several wake-related neurotransmitter receptors, including dopamine 1 (D1) receptor. Nevertheless, an intriguing point highlights that MOD might be activating intracellular elements bounded to D1 receptor, such as cAMP response element-binding (CREB) or mitogen-activated protein kinase (MAP-K) expression...
December 14, 2016: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/27894244/umbelliferone-decreases-intracellular-ph-and-sensitizes-melanoma-cell-line-a375-to-dacarbazin-comparison-with-acetazolamide
#11
Clémentine Puech, Morgane Chatard, Delphine Felder-Flesch, Nathalie Prevot, Nathalie Perek
The high degree of malignancy of tumour cells is linked to alterations of many physiological parameters like the intracellular pH (pHi). The pHi in cancer cell line is regulated by the anhydrase carbonique IX (CA IX). The main enzymatic function of the CA IX protein is to catalyze the hydration of carbon dioxide into bicarbonate ions and protons. Inhibiton of transmembrane tumor associated isozyme carbonic anhydrase IX (CA IX) with specific inhibitors is a promising and expanding field as CA IX is involved in tumor progression...
November 28, 2016: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26768962/editorial-thematic-issue-new-insights-into-a-classical-pathway-key-roles-of-the-mevalonate-cascade-in-different-diseases-part-i
#12
EDITORIAL
Saeid Ghavami, Nicholas J Kenyon, Behzad Yeganeh, Amir A Zeki
No abstract text is available yet for this article.
2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26758950/roles-of-the-mevalonate-pathway-and-cholesterol-trafficking-in-pulmonary-host-defense
#13
Kristin A Gabor, Michael B Fessler
The mevalonic acid synthesis pathway, cholesterol, and lipoproteins play fundamental roles in lung physiology and the innate immune response. Recent literature investigating roles for cholesterol synthesis and trafficking in host defense against respiratory infection was critically reviewed. The innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense in the lung. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol...
2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26758949/mevalonate-cascade-and-its-regulation-in-cholesterol-metabolism-in-different-tissues-in-health-and-disease
#14
Mohammad Hashemi, Reyhane Hoshyar, Sudharsana R Ande, Qi M Chen, Claudia Solomon, Anne Zuse, Mohammad Naderi
The cholesterol biosynthesis pathway, also referred to as the mevalonate (MVA) pathway, is responsible for the biosynthesis of two key isoprenoids: farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational modification of small GTPases by FPP and GGPP has captured much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) catalyzes the conversion of HMG-CoA to MVA, and is the rate-limiting step in the biosynthesis of cholesterol...
2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26758946/basic-and-clinical-observations-of-mevalonate-depletion-on-the-mevalonate-signaling-pathway
#15
Alison L Muller, Darren H Freed
Inhibition of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by pharmaceuticals, commonly referred to as statins, has proven to be an effective and efficient way in reducing cholesterol levels in patients. As a result of this intervention, mevalonate production, formed during cholesterol synthesis, is inhibited. Mevalonate is the precursor to a variety of crucial downstream products, including those involved with the mitochondrial electron transport chain, and localized activation of small GTPases. Statins have also been observed to induce changes of the immune system, favouring a reduced proinflammatory phenotype...
2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26758945/clinical-studies-of-statins-in-asthma-and-copd
#16
Neil C Thomson
Immunomodulatory effects of statins in vitro and in experimental models of asthma and COPD could potentially be relevant to the treatment of chronic airway diseases. This article provides an overview of the evidence from the key clinical studies on the effects of statins on clinical outcomes and inflammatory biomarkers in asthma and COPD. Future directions for clinical studies of statins in asthma and COPD are discussed. A small number of randomized controlled trials (RCTs) in adults with mild to moderate asthma suggest that short-term statin treatment does not improve lung function or symptom control, except for a possible improvement in quality of life and symptoms in smokers with asthma...
2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/26758944/the-mevalonate-pathway-and-innate-immune-hyper-responsiveness-in-the-pathogenesis-of-copd-and-lung-cancer-potential-for-chemoprevention
#17
Robert P Young, Raewyn J Hopkins
Current evidence suggests that persisting and/or exaggerated inflammation in the lungs initiated by smoking, and up-regulated through genetic susceptibility, may result in lung remodelling and impaired repair. The mevalonate pathway, through its modifying effects on innate immune responsiveness, may be involved in these processes providing a plausible pathogenic link between the development of chronic obstructive pulmonary disease (COPD) and lung cancer. The mevalonate pathway, mediates these effects through important intra-cellular signalling molecules called guanine phosphate transferases (GTPases) such as Rho-A...
2017: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/27809751/structure-and-function-of-small-non-peptide-crf-antagonists-and-their-potential-clinical-use
#18
Hesham Fahmy, Bahimanna Kuppast, Mohamed Teleb Ismail
Corticotropin-releasing factor (CRF) can be considered a very important hormone or a chemical mediator. It works closely with other systems to regulate the manner through which the body may respond to stress. Thus it affect many biological processes associated with stress. Dysfunction of this system has also been correlated with various diseases such as major depression, anxiety, drug addiction and eating disorders. Rationally, this means that interfering with binding of CRF to its intended receptors can be an attractive target for drug design aiming at developing new medications for many ailments that are associated with stress such as depression, anxiety and stress-induced relapse in drug addiction...
November 1, 2016: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/27784217/role-of-central-and-peripheral-crh-in-skin
#19
Maria Venihaki, Olga Rassouli, George Liapakis
Hypothalamic corticotrophin-releasing hormone (CRH) has a key role in coordinating and controlling complex responses to stress, both systemically, by stimulating the expression of the pituitary POMC gene, and thus, resulting in increased production of ACTH and adrenal glucocorticoid release, and locally since CRH has been identified in several peripheral tissues. CRH seems to exert its effects through interaction with two known so far receptors, CRF1R and CRF2R. The mRNA and protein of CRH family of peptides and their receptors are expressed at several peripheral tissues including rodent and human skin...
October 26, 2016: Current Molecular Pharmacology
https://www.readbyqxmd.com/read/27550421/synergistic-effects-of-social-isolation-and-morphine-addiction-on-reduced-neurogenesis-and-bdnf-levels-and-the-resultant-deficits-in-cognition-and-emotional-state-in-male-rats
#20
Hamidreza Famitafreshi, Morteza Karimian, Sulail Fatima
INTRODUCTION: Addiction to drugs of abuse is a devastating condition which results in deterioration of brain function. On the other hand, social isolation also produces cognitive deficits such as learning and memory impairment. This study was designed to evaluate the potential negative synergistic effects of social isolation and morphine addiction on brain functions. METHODS AND MATERIAL: One hundred and two Sprague-Dawley rats were randomly divided into four groups for assessing neurogenesis and behaviour: group-housed, isolated, morphine-treated group-housed and morphine-treated isolated groups...
August 22, 2016: Current Molecular Pharmacology
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